For a virus to infect a cell and subsequently cause disease it must first bind to its cellular receptor. The Oldstone laboratory isolated and characterized the cellular receptor, alpha-dystroglycan ((-DG) for several arenaviruses including Lassa fever virus (LFV) and LCMV CI 13. We provided evidence that (-DG is the receptor required for infection (Cao et al., Science, 1998; Spiropoulou et al., J. Virol., 2002) as: 1) LFV and LFV glycoprotein (GP) bind at high affinity to purified (-DG immobilized on membranes; 2) normally permissive cells bearing a null mutation of the DG gene are resistant to LFV infection; 3) reconstitution of (-DG expression in null mutant cells using an adenovirus vector restored susceptibility to LFV. We have established a high-output assay to analyze LFVGP-mediated infection of target cells under BSL2 conditions. In the Boger laboratory solution-phase synthetic techniques have been utilized to create unique combinatorial libraries of small molecules that can be screened to identify therapeutic compounds that promote protein-protein interactions (agonists) or inhibit protein-protein interactions (antagonists). We propose three specific aims: First, to screen combinatorial chemical libraries to discover small molecules that inhibit LFVGP-mediated infection of cells using retroviral vectors that contain LFVGP in their envelope and a green fluorescent protein reporter gene. Second, to develop a drug that would neutralize free LFV by engineering anti-viral receptor-bodies, in which the Fab part of an IgG molecule is replaced by a virus-binding (-DG fragment. Third, to validate this inhibition in vivo by blocking LCMV CI 13 infection in a mouse model (CI 13 and LFV binds at high affinity to (-DG and predictably utilizes the same binding site). Final verification would be done at CDC using the experimentally defined chemical inhibitor(s) and virulent LFV.